An incredible paper which may turn diabetes treatment on its head

First off, why should a neurologist be interested in diabetes? That’s for endocrinologists isn’t it? Not really. One of the most serious aspects of diabetes is its acceleration of vascular disease (atherosclerosis), with an increased risk of heart attack and stroke (which is where the neurologist comes in). So you have a diabetic who has survived a stroke. You want to prevent the next one, and you know that they’re in a much higher risk group for another stroke (1) because they just had one (2) because they’re more likely to have another because of their diabetes. Also vascular disease makes any neurologic problem worse, dementia, neuropathy you name it.

So I’ve always tried to stay current on diabetes. Which brings me to Proc. Natl. Acad. Sci. vol. 109 pp. 14972 – 14976 ’12 (11 September issue). You’d think that nearly a century after Banting and Best’s discovery of Insulin that there were no new wrinkles left. Not so.

Now for a bit of anatomy and physiology. In a very simplistic way, you can regard diabetes as not enough insulin. Insulin lowers blood sugar and is needed after you eat. It is made in the pancreas, an organ which secretes digestive enzymes into your gastrointestinal tract. It also secretes insulin, but into the blood rather than the gut. Insulin is made in relatively small collections of cells (1,000 – 10,0000) called islets dispersed through out the pancreas. They are .1 – .2 milliMeters in diameter, and even though we have over 1,000,000 of them, they constitute 2% of the mass of the pancreas. 85% of the islet cells make insulin (the beta cells), another cell type (the alpha cells) make another protein (glucagon), also secreted into the blood, making it a hormone by definition. Glucagon raises blood sugar, by causing the liver to make glucose and then pump it out.

Streptozotocin (a glucose derivative) made by soil bacteria, has the nasty property of selectively killing pancreatic beta cells, leaving everything else alone. Naturally experimentalists love it and have used it to produce severe diabetes (fatal if untreated) in lab animals, and then try new treatments to see if they can come up with something better.

Amazingly, here’s one they didn’t try until now. Given our present tools, you can pretty much knock out any gene you want in a mouse embryonic stem cell, implant it in another mouse, and (after a lot of failure), make a strain of mice lacking that particular gene (these are what’s called knockout mice). What they knocked out was not glucagon (which has effects all over the body, including the brain), but the receptor for glucagon. So even though there’s plenty of glucagon around, lacking the receptor cells don’t respond to it. It’s like hearing a language you don’t know — the sound is there all right but you can’t internalize it and react to what’s being said.

It had been known for a while that giving streptozotocin to mice lacking the glucagon receptor doesn’t produce diabetes (or much else). The finding as been treated with a good deal of skepticism, being blamed on other factors. The authors of the present paper, found a way to put the glucagon receptor back into the liver (using a virus). When they did this to a knockout mouse living happily despite being treated with strpetozotocin, their glucose shot up. The virus didn’t hang around forever, glucagon receptor levels in the liver dropped and blood sugar dropped along with it. Remember that a normal mouse dies of diabetic complications fairly quickly after receiving streptozotocin.

You couldn’t ask for much better proof, and a new way to treat diabetes may have been found. Amazing.

As in all of medicine there are caveats. The glucagon receptor is found in other organs, heart and brain among them, so blocking the action of glucagon this way may have many other effects.

Comments

So basically this paper nicely makes an argument in favor of glucagon receptor antagonists? If I remember correctly this idea has been around for some time (for eg. see http://www.ncbi.nlm.nih.gov/pubmed/12476962). I would indeed be worried about the side effects of blocking a universal receptor, although this strategy is certainly not unknown.

Thanks. If you look at the discussion of the cited paper, they note that these results have been around for a while, but dismissed as due to some other effect of the knockout — which certainly happens with knockouts, particularly since the gene is knocked out throughout embryogenesis etc. etc. The great thing about this paper is that they put the receptor back into the liver (using a virus), watched the diabetes go out of control, and then, since the virus just brought the mRNA into the cell, but not the gene, watched the level of the receptor drop, and the sugar come back down. Very impressive (to me).

Speaking of new diabetes treatments, take a look at the following paper in Cell (Talchai et al. 2012. Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell Failure. Cell 150(6):1223), which suggest that in type 2 diabetes, the islet cells are not dying, but rather reverting to an undifferentiated state. If these findings hold up, they suggest reversing the dedifferntiation process a new way of treating diabetes.

Yes, I saw that one as well. Somewhat scarred by the results of messing around with differentiating more primitive cells (e.g. reversing the de-differentiation). When tried for Parkinsonism using transplants into the brain some of them formed tumors.

[ J. Neurosurg. vol. 89 pp. 592 – 598 ’98 ] A 52 year old woman (Japanese) had fetal dopamine neurons put into her putamen 2 years later she presented in a coma. There was an enhancing mural nodule with a large cyst arising from the left putamen causing brainstem compression (the grafts were bilateral). The cells of the cyst wall were from the graft. (Outcomes have been reported for about 50 patients with fetal transplantation and most of them are around 6 months). This is the second reported death attributable to aberrant growth of fetal tissue .

Reblogged this on The Diabetes World Reader and commented:
I found this to be a fascinating post for those already suffering the complications of their disease. With diabetes we all need the services of multiple specialists, not just the endocrinologist.